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Title: A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias
Authors: Cortes, J.E.
Kim, D.-W.
Pinilla-Ibarz, J.
Le Coutre, P.
Paquette, R.
Chuah, C. 
Nicolini, F.E.
Apperley, J.F.
Khoury, H.J.
Talpaz, M.
DiPersio, J.
DeAngelo, D.J.
Abruzzese, E.
Rea, D.
Baccarani, M.
Müller, M.C.
Gambacorti-Passerini, C.
Wong, S.
Lustgarten, S.
Rivera, V.M.
Clackson, T.
Turner, C.D.
Haluska, F.G.
Guilhot, F.
Deininger, M.W.
Hochhaus, A.
Hughes, T.
Goldman, J.M.
Shah, N.P.
Kantarjian, H.
Issue Date: 2013
Citation: Cortes, J.E., Kim, D.-W., Pinilla-Ibarz, J., Le Coutre, P., Paquette, R., Chuah, C., Nicolini, F.E., Apperley, J.F., Khoury, H.J., Talpaz, M., DiPersio, J., DeAngelo, D.J., Abruzzese, E., Rea, D., Baccarani, M., Müller, M.C., Gambacorti-Passerini, C., Wong, S., Lustgarten, S., Rivera, V.M., Clackson, T., Turner, C.D., Haluska, F.G., Guilhot, F., Deininger, M.W., Hochhaus, A., Hughes, T., Goldman, J.M., Shah, N.P., Kantarjian, H. (2013). A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. New England Journal of Medicine 369 (19) : 1783-1796. ScholarBank@NUS Repository.
Abstract: BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE number, NCT01207440.) Copyright © 2013 Massachusetts Medical Society.
Source Title: New England Journal of Medicine
ISSN: 00284793
DOI: 10.1056/NEJMoa1306494
Appears in Collections:Staff Publications

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